US4277470A - Heterocyclic spiro-linked amidines, compositions and use thereof - Google Patents
Heterocyclic spiro-linked amidines, compositions and use thereof Download PDFInfo
- Publication number
- US4277470A US4277470A US06/123,200 US12320080A US4277470A US 4277470 A US4277470 A US 4277470A US 12320080 A US12320080 A US 12320080A US 4277470 A US4277470 A US 4277470A
- Authority
- US
- United States
- Prior art keywords
- spiro
- bicyclo
- pyrroline
- heptane
- morpholino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/05—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/96—Spiro-condensed ring systems
Definitions
- the invention relates to a new class of heterocyclic spiro-linked amidines which have a powerful antidepressant action, processes for the preparation of these new compounds, new intermediate products which are suitable for the preparation of the active compounds according to the invention, and pharmaceutical agents which contain the active compounds according to the invention and the use thereof as medicaments for the treatment of depressive conditions.
- the invention relates to heterocyclic, spiro-linked amidines of the formula I ##STR2## in which n is 1 or 2; R 1 and R 2 denote hydrogen or alkyl radicals, which, together with the nitrogen, can form a 5-, 6- or 7-membered ring which can be substituted by C 1 -C 3 -alkyl, C 1 -C 2 -alkoxy, hydroxyl or C 1 -C 4 -alkoxycarbonyl groups and in which one of the carbon atoms can also be replaced by an oxygen, sulfur or nitrogen atom, it being possible for the nitrogen atom to be substituted by hydrogen, the formyl group or a phenyl radical, which can in turn be monosubstituted or polysubstituted by a C 1 -C 4 -alkyl group or an alkoxy, methylenedioxy, hydroxyl, halogen, nitro or amino group, or it being possible for the nitrogen atom to be substituted by a C 1 -C
- the invention also relates to the compounds used as intermediate products, of the formula II ##STR3## in which n, R 3 and R 4 have the meanings given for formula I and Z denotes a halogen atom or a SH, SR 5 or OR 5 radical, in which R 5 represents a C 1 -C 6 -alkyl, benzyl, phenylalkyl or phenylsulfonyl radical.
- the preparation of the compounds of the formula I according to the invention by process a is carried out at a temperature of 0°-120° C., preferably at 50° C., in an inert solvent, preferably benzene, toluene, chloroform, carbon tetrachloride, trichloroethylene or dioxan.
- an inert solvent preferably benzene, toluene, chloroform, carbon tetrachloride, trichloroethylene or dioxan.
- a compound of the formula II is dissolved in an inert solvent, preferably diethylene glycol dimethyl ether, dioxan, dimethylformamide or tetrahydrofuran, and either the gaseous amine is passed into this solution or the liquid or dissolved amine is added to the solution.
- an inert solvent preferably diethylene glycol dimethyl ether, dioxan, dimethylformamide or tetrahydrofuran
- the reaction is carried out either with cooling, or at room temperature, or at moderately elevated temperatures.
- a compound of the formula V is reacted with an alkylating agent, for example an alkyl halide or an alkyl sulfate or dialkyl sulfate, by customary and known methods, or is reacted by other customary processes, for example in accordance with the method of Leuchart-Wallach.
- an alkylating agent for example an alkyl halide or an alkyl sulfate or dialkyl sulfate
- the reaction in process d is preferably carried out in dry pyridine at a temperature of -30° C. to 20° C., preferably at -10° C. (H. Henecka, P. Kurtz, Houben-Weyl, Methoden der organischen Chemie, Sauerstoff füren III (Methods of Organic Chemistry, Oxygen Compounds III), Volume 8, page 704 (1952)).
- phosphorus pentahalides are reacted with compounds of the formula III in an anhydrous inert organic solvent, such as dioxan, chloroform, carbon tetrachloride or trichloroethylene, at temperatures of -40° C. to 50° C., preferably at -10° C.
- anhydrous inert organic solvent such as dioxan, chloroform, carbon tetrachloride or trichloroethylene
- suitable alkylating agents are alkyl halides, preferably methyl iodide and ethyl bromide, and furthermore diesters of sulfuric acid or of toluenesulfonic acid.
- Alcohols such as methanol, or tetrahydrofuran or dioxan are preferably used as the solvent, and acetone is particularly preferably suitable.
- the reaction temperature is between 0° C. and the boiling point of the solvent chosen, and is preferably 30°-60° C.
- the triethyloxonium fluoborate obtainable from boron trifluoride-etherate and epichlorohydrin (compare H. Meerwein et al., J.pr. Chem.(2), 147 257 (1937); and 154, 83 (1939)), used in process c' is reacted in situ with a compound of the formula III.
- Diethyl ether or halogenated hydrocarbons, for example carbon tetrachloride are particularly suitable solvents.
- the reaction temperature is between 0° C. and the boiling point of the solvent used, and is preferably 30°-40° C.
- the reaction temperature is 0° C.-60° C., preferably 30°-40° C.
- reaction of compounds of the formula III with phosphorus pentasulfide by process e' is carried out in a suitable solvent, such as, for example, pyridine or toluene, and with calcium oxide as a basic catalyst, at 20°-120° C., preferably at 50° C.
- a suitable solvent such as, for example, pyridine or toluene
- calcium oxide as a basic catalyst
- nitro-bicyclic compounds of the formula VII in which R 3 and R 4 have the meaning given for formula I can be prepared by a Diels-Alder reaction from corresponding ⁇ -nitrostyrenes in boiling cyclopentadiene (Literature: J.Org. Chem. 26, 4898 (1961); 8, 373 (1943); and J. Amer.Chem.Soc. 73, 5068 (1951)).
- the Michael addition of methyl acrylate onto nitro compounds of the general formula VII with the addition of a base, preferably benzyl-trimethylammonium hydroxide, is carried out in an alcohol, such as methanol, or tetrahydrofuran, but preferably in tert.-butanol or dioxan, at 0°-120° C., preferably at 10°-100° C.
- a base preferably benzyl-trimethylammonium hydroxide
- the 2-nitrobicyclo[2.2.2]oct-5-enes X which are known from the literature, can be prepared from the ⁇ -nitrostyrenes and an excess of 1,3-cyclohexadiene.
- the starting compounds can be further processed in the crude form.
- compounds according to the invention which can be prepared are, preferably, the following: 5'-(4-phenylpiperidino)-3-phenyl-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline], 3-phenyl-5'-thiamorpholino-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline], 3-(4-chlorophenyl)-5'-(2-methylpiperidino)-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline], 3-(4-chlorophenyl)-5'-(3-methylpiperidino)-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline], 3-(4-chlorophenyl)-5'-(4-methylpiperidino)-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline], 3-(4
- the compounds of the formula I can exist in four stereoisomeric forms and each stereoisomer can exist in two enantiomeric forms. It has now been found that in the preparation of the compounds of the formula I according to the invention, the stereoisomeric exo-aryl-endo-spiropyrroline compounds of the general formula XII ##STR10## in which n, R 1 , R 2 , R 3 and R 4 have the meanings given for formula I, are formed as the main product.
- the configuration of the compounds of the general formula I is determined by the stereochemistry of the nitro-bicyclic compounds of the formulae XIII and XIV used as starting materials. ##STR11##
- optical isomers of the heterocyclic spiro-linked amidines of the formulae XII and XVII display surprisingly unusual differences in their biological activity.
- the anti-depressant activity of the laevorotatory isomer is more highly pronounced, whilst the dextro-rotatory isomer has a weaker action than the racemate.
- the present invention thus also relates to optically active stereoisomers of compounds of the general formulae XII and XVII in which R 1 , R 2 , R 3 and R 4 have the meanings indicated for formula I, as well as the acid addition salts thereof, processes for the preparation of these compounds and pharmaceutical formulation containing them.
- optically active stereoisomers are: (-)-3-exo-(4-chlorophenyl)-5'-morpholino-spiro[bicyclo[2.2.1]-heptane-2,2'-5-endo-pyrroline], (-)-3-endo-(4-chlorophenyl)-5'-morpholino-spiro[bicyclo[2.2.1]-heptane-2,2'-5-exo-pyrroline], (-)-3-exo-(4-chlorophenyl)-5'-morpholino-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-5-endo-pyrroline], (-)-3-endo-(4-chlorophenyl)-5'-morpholino-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-5-exo-pyrroline], (-)-3-endo-(4-chlorophenyl)-5'-morpholino-
- optical isomers according to the invention can be prepared by resolving either a racemic compound of the abovementioned formulae XII and XVII, in which n, R 1 , R 2 , R 3 and R 4 have the meanings indicated, or a racemic precurser thereof into the optical isomers by a standard process, and if necessary converting the optically active precurser thus obtained into the desired compounds of the formulae XII or XVII.
- a racemic mixture of a compound of the abovementioned formulae XII and XVII is resolved into the optical isomers by a standard resolution process, such as is described in the literature.
- the resolution can, of course, also be carried out with a racemic mixture of the end product or with a racemate of an intermediate compound of the general formula V, in which case one or both of the optical isomers ar reacted further.
- the resolution is in general carried out on a racemic mixture of the basic compound of the general formula XII and XVII by processes described in the literature, for example using an optically active acid.
- a solution of the racemate in a suitable solvent for example an alcohol
- a solution of an optically active acid in order to effect crystallization of the salt of a specific enantiomer.
- the other enantiomer can frequently be prepared from the mother liquors, if desired by treatment with a base and then with the other optical isomer of the optically active acid, or it is also possible to treat a fresh solution of the racemate with a solution of the other enantiomorph of the optically active acid.
- the particular solvent to be used in an individual case and the particular optically active acid to be used cannot be generally predicted and the correct choice is made with the aid of simple experiments.
- the best combination is that whereby it is possible to isolate the salt in a highly pure state (that is to say free from the other enantiomer) and as crystals.
- D(-)- and L(+)-tartaric acid, D(-)- and L(+)-dibenzoyltartaric acid and D(-)- and L(+)-di-p-tolyltartaric acid are very particularly suitable for the resolution of some compounds of the formulae XII and XVII.
- the compounds of the formula I or their stereoisomers of the formulae XII and XVII can be isolated as such or in the form of an acid addition salt by the processes described.
- the salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as, for example, those with inorganic acids, such as hydrochloric acid, hydrobromic acid and hydriodic acid, nitric acid, sulfuric acid or phosphoric acid, or with organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, glycolic acid, lactic acid, malonic acid, hydroxymaleic acid, fumaric acid, oxalic acid, citric acid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, embonic acid, naphthalene-1,5-disulfonic acid, ascorbic acid, phenylacetic acid, p-amino-salicyclic acid, hydroxyethan
- the acid addition salt thereby obtained can be converted into the free compound by known processes, for example by treatment with a base, such as a metal hydroxide, metal alcoholate or metal carbonate, with ammonia or with a hydroxyl ion exchanger, or with any other suitable reagent.
- a resulting acid addition salt can be converted into another salt by known processes; thus, for example, a salt with an inorganic acid can be treated with a metal salt, such as, for example, a sodium salt, barium salt or silver salt, of and acid in a suitable diluent in which the resulting inorganic salt is insoluble and the inorganic salt is thereby removed from the reaction medium.
- An acid addition salt can also be converted into another acid addition salt by treatment with an anion exchanger preparation.
- a quaternary ammonium salt can be prepared by reacting the free base with an alkyl halide.
- the compounds according to the invention and their pharmacologically acceptable salts antagonize tetrabenazine ptosis in mice, with an ED 50 of 0.1-10 mg/kg: the appropriate amount of a 1% strength homogenate of the test substance (in carboxymethylcellulose) in a 0.9% strength NaCl solution (in distilled water) is administered to five male animals weighing 22 g, whereupon the ptosis caused by tetrabenazine administered beforehand is cured.
- the anti-depressant activity and their use for the treatment of various depressive states in mammals was furthermore demonstrated with the aid of the inhibition of the resorption of noradrenalin and dopamine in cases of cerebral synaptosomes in mice.
- the compounds have a low toxicity.
- the LD 50 values are in general between 100-500 mg/kg on oral administration (mice).
- the compounds according to the invention and their pharmaceutically acceptable salts are active within a broad dosage range, the particular dose administered depending on various factors, such as, for example, the particular compound used and the condition, type and size of the mammal to be treated.
- the dose required per day is usually within the range from 10 to 60 mg in the treatment of adult humans.
- compositions according to the invention and their salts are usually administered orally or by injection, and for this purpose these compounds and salts are as a rule used in the form of a pharmaceutical preparation.
- These pharmaceutical agents are prepared in a manner which is in itself known in this field, and they usually contain at least one compound according to the invention or a salt thereof in combination with a pharmaceutically acceptable excipient suitable for this purpose.
- the active constituent is as a rule mixed with an excipient or diluted with an excipient or enclosed in an excipient, which can be in the form of a capsule, in the form of a sachet or in the form of another container; if the excipient serves as the diluent, it can be a solid, semi-solid or liquid material which is used as a diluent, auxiliary or medium for the active constituent (active compound).
- excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl and propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.
- the pharmaceutical agents according to the invention can be formulated in a manner which is in itself known such that they release the active compound, after administration, to the patient rapidly, continuously or in a delayed manner.
- the pharmaceutical agents indicated above can be processed to tablets, capsules or suspensions for oral use and to injection solutions for parenteral use.
- the invention accordingly furthermore relates to a pharmaceutial agent (preparation), which contains at least one compound of the formula I or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable excipient suitable for this purpose.
- the present invention relates to a process for the treatment of depressive states in mammals, in particular humans, which comprises administering a compound of the formula I, or of a pharmaceutically acceptable salt thereof, to the sick person in an amount having an anti-depressant effect.
- the compound thus prepared is an exo-aryl-endo-spiropyrroline compound froma stereochemical point of view, as also are all the other compounds of Table 1, which were prepared analogously.
- heterocyclic spiro-linked amidines and their precursors have the exo-aryl-endo-pyrroline configuration.
- Example 73 The compound of Example 73 is also prepared analogously to Example 1:
- 3-Phenyl-5'-piperidino-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-5-pyrroline] hemi-naphthalene-1,5-disulfonate can be prepared analogously to Example 75in the form of colorless crystals of melting point 176° C.
- Variant A 0.14 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene is dissolved in 50 ml of dioxan, with the addition of 27 ml of Triton B and 0.14 mole of methyl acrylate, and the mixture is refluxed until the reaction is complete (4 hours). After stripping off the solvent, the residue crystallizes completely. Recrystallization from isopropanol gives crystals of melting point 127°-132° C.
- Variant B 0.18 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene, 0.18 mole of methyl acrylate and 3.8 ml of Triton B in 50 ml of tert.-butanol and stirred for 24 hours, a further 0.18 mole of methyl acrylate and 70 mlof dioxan are then added and the mixture is heated to the reflux temperature for 24 hours. After cooling, the reaction mixture crystallizes. A little ethanol is added, the mixture is neutralized with 2N hydrochloric acid and the crystal sludge is filtered. Recrystallization of the crystals from isopropanol with the addition of animal charcoal gives crystals of melting point 127°-131° C.
- Example 80 The compounds of Examples 80 and 81 are prepared analogously to Example 79.
- the D,L-3-exo-(4-fluorophenyl)-5'-morpholino-spiro[bicyclo[2.2.1]-heptane-2,2'-5-endo-pyrroline] hydriodide obtained, from ethanol, according to Example 45 is converted to the salt-free form by extraction by shaking with 2 N potassium hydroxide solution/methylene chloride in the customary manner.
- the oil (10.7 g) obtained after drying, filtering and evaporating the organic phase is dissolved in 185 ml of methanol, and 4.9 g of D(-)-tartaric acid in 60 ml of water are slowly added, whilst stirring.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2907070 | 1979-02-23 | ||
DE19792907070 DE2907070A1 (de) | 1979-02-23 | 1979-02-23 | Heterocyclische spiroverknuepfte amidine und verfahren zu ihrer herstellung |
Publications (1)
Publication Number | Publication Date |
---|---|
US4277470A true US4277470A (en) | 1981-07-07 |
Family
ID=6063739
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/123,200 Expired - Lifetime US4277470A (en) | 1979-02-23 | 1980-02-21 | Heterocyclic spiro-linked amidines, compositions and use thereof |
Country Status (11)
Country | Link |
---|---|
US (1) | US4277470A (es) |
EP (1) | EP0014996B1 (es) |
JP (1) | JPS55120563A (es) |
AT (1) | ATE914T1 (es) |
AU (1) | AU534240B2 (es) |
CA (1) | CA1140930A (es) |
DE (2) | DE2907070A1 (es) |
DK (1) | DK77280A (es) |
ES (5) | ES488705A1 (es) |
IL (1) | IL59441A0 (es) |
ZA (1) | ZA801041B (es) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4543355A (en) * | 1981-12-22 | 1985-09-24 | Sumitomo Chemical Company, Limited | Substituted succinimides, compositions and method of use |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9904121D0 (sv) | 1999-11-15 | 1999-11-15 | Gustaf Jederstroem | Hydrophobe biomolecular structure |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2931805A (en) * | 1958-11-10 | 1960-04-05 | Smith Kline French Lab | Spiro [bicyclo [2. 2. 1] heptane-2, 2'-alkylenimines] |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2911409A (en) * | 1955-07-18 | 1959-11-03 | Upjohn Co | 2-spiro-substituted pyrrolidines |
-
1979
- 1979-02-23 DE DE19792907070 patent/DE2907070A1/de not_active Withdrawn
-
1980
- 1980-02-18 ES ES488705A patent/ES488705A1/es not_active Expired
- 1980-02-18 ES ES488702A patent/ES488702A1/es not_active Expired
- 1980-02-18 ES ES488703A patent/ES488703A1/es not_active Expired
- 1980-02-18 ES ES488704A patent/ES488704A1/es not_active Expired
- 1980-02-18 ES ES488706A patent/ES488706A1/es not_active Expired
- 1980-02-20 EP EP80100835A patent/EP0014996B1/de not_active Expired
- 1980-02-20 AT AT80100835T patent/ATE914T1/de not_active IP Right Cessation
- 1980-02-20 DE DE8080100835T patent/DE3060314D1/de not_active Expired
- 1980-02-21 US US06/123,200 patent/US4277470A/en not_active Expired - Lifetime
- 1980-02-21 IL IL59441A patent/IL59441A0/xx unknown
- 1980-02-22 CA CA000346308A patent/CA1140930A/en not_active Expired
- 1980-02-22 AU AU55806/80A patent/AU534240B2/en not_active Ceased
- 1980-02-22 DK DK77280A patent/DK77280A/da not_active Application Discontinuation
- 1980-02-22 JP JP2067380A patent/JPS55120563A/ja active Pending
- 1980-02-22 ZA ZA00801041A patent/ZA801041B/xx unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2931805A (en) * | 1958-11-10 | 1960-04-05 | Smith Kline French Lab | Spiro [bicyclo [2. 2. 1] heptane-2, 2'-alkylenimines] |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4543355A (en) * | 1981-12-22 | 1985-09-24 | Sumitomo Chemical Company, Limited | Substituted succinimides, compositions and method of use |
Also Published As
Publication number | Publication date |
---|---|
ES488706A1 (es) | 1980-09-16 |
ES488703A1 (es) | 1980-09-16 |
DE3060314D1 (en) | 1982-06-09 |
ZA801041B (en) | 1981-03-25 |
ATE914T1 (de) | 1982-05-15 |
CA1140930A (en) | 1983-02-08 |
AU5580680A (en) | 1980-08-28 |
ES488702A1 (es) | 1980-09-16 |
DK77280A (da) | 1980-08-24 |
JPS55120563A (en) | 1980-09-17 |
AU534240B2 (en) | 1984-01-12 |
DE2907070A1 (de) | 1980-09-04 |
EP0014996B1 (de) | 1982-04-28 |
EP0014996A1 (de) | 1980-09-03 |
IL59441A0 (en) | 1980-05-30 |
ES488704A1 (es) | 1980-09-16 |
ES488705A1 (es) | 1980-09-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DK175839B1 (da) | Forbindelser af typen 6H-benzfuro[3a,3,-ef][2]benzazepin samt anvendelse af disse til behandling af Alzheimer's syge | |
EP0025111B1 (en) | 3-aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them | |
UA81749C2 (uk) | Фенілпіперазинові похідні як інгібітори зворотного захоплення серотоніну | |
DE68922478T2 (de) | Pyrazoloisoquinoline-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen. | |
US4420480A (en) | Hexahydronaphth[1,2-b]-1,4-oxazines | |
EP0414422A2 (en) | 2-Oxo-1-oxa-8-azaspiro [4,5] decane derivatives, processes for their preparation and pharmaceutical compositions thereof | |
DE69007900T2 (de) | 4,4-Disubstituierte Piperidinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen. | |
US4277470A (en) | Heterocyclic spiro-linked amidines, compositions and use thereof | |
KR870001681B1 (ko) | 히단토인 유도체의 제조방법 | |
US3936459A (en) | 1',4'-Dihydro-1-methyl-spiro [piperidine and pyrrolidine-2,3'(2'H)quinoline]-2'-one compounds | |
KR830001667B1 (ko) | 페닐 퀴놀리지딘의 제조방법 | |
HRP920778A2 (en) | Novel 1-oxa-2-oxo-8-azaspiro74,5/ decane derivatives, pharmaceutical preparations containing them and process for the preparation thereof | |
US3960872A (en) | 1 Alkyl-4-(10:oxo or hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine compounds | |
JP2956788B2 (ja) | スピロイソインドリン化合物、その製造方法、それを含有する神経症を治療するための医薬およびそれを製造するための中間体 | |
PL94151B1 (es) | ||
US4318909A (en) | Benzoxazocines | |
KR850001038B1 (ko) | 알로파노일 피페라진 화합물의 제조방법 | |
US4626522A (en) | Benzoxazocines intermediates | |
US3968115A (en) | 1-Alkyl-4-(10 and/or 11)-bromo-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ylidene piperidine compounds | |
JPS62190156A (ja) | ベンゼン融合β−ジケトシクロアルキレンの対称性O−置換ジオキシム、それらの調製方法およびそれらの薬物への適用 | |
US3655680A (en) | Method for the production of the (+)-optical isomer of alpha-racemate 2-(2-ethyl-2-phenyl-1 3-dioxolan-4-yl)-piperidine | |
IL29176A (en) | Benzylpyridinium compounds,their preparation and pharmaceutical preparations containing them | |
GB2115811A (en) | Ergot alkaloids | |
US3981876A (en) | 1-Alkyl-4-(10[1-piperidyl]-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine compounds | |
KR840000498B1 (ko) | 복소환식 스피로-결합 아미딘의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |